Abstract The retinal tissue requires an adequate supply of oxygen and nutrients to maintain normal metabolism and function. Insufficient blood flow (ischemia) leads to reduced tissue oxygenation (hypoxia), development of pathologies, and ultimately tissue loss. Hypoxia-triggered pathologies can cause visual impairment in many retinal diseases, including vascular occlusions, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and glaucoma. Several factors, including vascular malperfusion, oxygen supply to demand adequacy, tissue hypoxia, and impaired energy metabolism contribute to vision loss. In order to gain knowledge of the relation among these factors, measurements of retinal oxygen delivery, oxygen extraction fraction, tissue oxygen tension and oxygen metabolism are required. Indeed, a combined and correlative evaluation of these key retinal oxygen metabolic-related parameters (oxygen delivery, oxygen extraction fraction, tissue oxygen tension, oxygen metabolism) is essential to understand the role of oxygen deficiency in the development of vision-threatening pathologies. The objective of the research project is to advance knowledge of retinal disease pathophysiology by a comprehensive and innovative investigation of retinal oxygen dynamics with the use of novel imaging technologies. The specific aims are to: 1) identify retinal oxygen metabolic-related parameters measured immediately after ischemia that can predict subsequent tissue outcomes; 2) elucidate compensatory capacities and consequent susceptibility of diabetic retina to impaired oxygen metabolism; 3) establish a threshold for retinal tissue injury based on the relation of the level and duration of ischemia to subsequent tissue outcomes; 4) determine alterations in edematous retinal tissue oxygenation and its response to light flicker-induced increased metabolic activity. The findings will impact the field by identifying clinically translatable markers to improve diagnostic/prognostic evaluation of retinal vascular occlusions, diabetic retinopathy and macular edema, as well as, propel development of preventative/therapeutic procedures that can successfully combat vision loss, thus improving the quality of life and reducing the cost of caring for the visually impaired.